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Review
. 2018 Dec 28:12:303-308.
doi: 10.2147/OTT.S182443. eCollection 2019.

Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy

Samah Nassereddine  1   2 , Coen J Lap  2 , Imad A Tabbara  1   2
Affiliations
Review

Evaluating ivosidenib for the treatment of relapsed/refractory AML: design, development, and place in therapy

Samah Nassereddine et al. Onco Targets Ther. .

Abstract

Improvements in the last decade in understanding the molecular mechanisms underlying acute myeloid leukemia (AML) have emphasized that treatment regimens should be personalized with agents that can selectively target genetic abnormalities if present. Neomorphic mutations in isoform 1 of isocitrate dehydrogenase (IDH1) result in the formation of the onco-metabolite R-2-hydroxyglutarate, which drives leukemic transformation by affecting processes such as chromatin remodeling, the cellular defense against oxidative stress and cell survival. Preclinical studies with small molecule inhibitors have validated mutant IDH1 as a molecular target, and a recent Phase 1 clinical trial with the first mutant IDH1 inhibitor ivosidenib has prompted approval by the US Food and Drug Association for the treatment of patients with IDH1-mutated AML in the relapsed and refractory setting due to impressive results. This approval has given a group of patients, that otherwise has a very poor prognosis and limited options, new hope, and it is to be expected that more indications for ivosidenib will follow soon. These developments highlight the potential of precision medicine in AML, with more agents currently under evaluation in clinical trials. Although the first reports have also already emerged describing acquired resistance for these mutant IDH inhibitors, combination treatment might overcome this problem, which could drastically change the treatment landscape of AML over the next few years.

Keywords: AML; IDH1; ivosidenib; refractory; relapsed.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
R-2HG promotes leukemogenesis through various mechanisms. Mutated IDH is able to convert the reaction that results in the formation of R-2-HG. Competitive inhibition of multiple classes of α-KG-dependent dioxygenases disrupts DNA methylation and histone methylation resulting in widespread epigenetic abnormalities and a global dysregulation of gene expression. Alternative mechanisms that promote transformation include aberrant HIF-1a signaling and cellular dependency on anti-apoptotic BCL-2. Ivosidenib is a direct inhibitor of mutant thereby preventing the formation of R-2-HG. Venetoclax binds and neutralizes BCL-2. Abbreviations: α-KG, α-ketoglutarate; R-2-HG, R-2 Hydroxyglutarate; TET, ten-eleven translocation; BCL-2, B-cell lymphoma 2.
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